Increased GABAergic Tone in the Ventromedial Hypothalamus Contributes to Suppression of Counterregulatory Reponses After Antecedent Hypoglycemia

Abstract

OBJECTIVE-We have previously demonstrated that modulation of ␥-aminobutyric acid (GABA) inhibitory tone in the ventromedial hypothalamus (VMH), an important glucose-sensing region in the brain, modulates the magnitude of glucagon and sympathoadrenal responses to hypoglycemia. In the current study, we examined whether increased VMH GABAergic tone may contribute to suppression of counterregulatory responses after recurrent hypoglycemia.RESEARCH DESIGN AND METHODS-To test this hypothesis, we quantified expression of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), in the VMH of control and recurrently hypoglycemic rats. Subsequently, we used microdialysis and microinjection techniques to assess changes in VMH GABA levels and the effects of GABA A receptor blockade on counterregulatory responses to a standardized hypoglycemic stimulus. RESULTS-QuantitativeRT-PCR and immunoblots in recurrently hypoglycemic animals revealed that GAD 65 mRNA and protein were increased 33 and 580%, respectively. Basal VMH GABA concentrations were more than threefold higher in recurrently hypoglycemic animals. Furthermore, whereas VMH GABA levels decreased in both control and recurrently hypoglycemic animals with the onset of hypoglycemia, the fall was not significant in recurrently hypoglycemic rats. During hypoglycemia, recurrently hypoglycemic rats exhibited a 49 -63% reduction in glucagon and epinephrine release. These changes were reversed by delivery of a GABA A receptor antagonist to the VMH. CONCLUSIONS-Our data suggest that recurrent hypoglycemia increases GABAergic inhibitory tone in the VMH and that this, in turn, suppresses glucagon and sympathoadrenal responses to subsequent bouts of acute hypoglycemia. Thus, hypoglycemia-associated autonomic failure may be due in part to a relative excess of the inhibitory neurotransmitter, GABA, within the VMH.

Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia

“…Plasma glucose concentrations were maintained at virtually identical levels (6.3 ± 0.8 mM) in the control and 3dRH groups during the hyperinsulinemic-euglycemic clamp ( Figure 2A). Nevertheless, the rats exposed to antecedent recurrent hypoglycemia required a nearly 2-fold higher glucose infusion rate to achieve the same level of glycemia ( Figure 2B), consistent with their previously reported impaired counterregulatory response (15)(16)(17). Plasma glucose 13 C enrichment was completely suppressed under these experimental conditions, allowing us to specifically assess the contribution of lactate to brain metabolism alone.…”

“…The objective of this study was to define the adaptations of neuronal lactate metabolism to antecedent recurrent hypoglycemia in our 3dRH rodent model, which has been well characterized by our group to reproduce the central neurotransmitter and hormonal adaptations and characteristic loss of counterregulation to acute hypoglycemia (15)(16)(17). For this purpose, we used nuclear magnetic resonance spectroscopy to measure the concentrations and enrichment of energy substrates and their metabolites with the nonradioactive stable isotope carbon-13 over time.…”

Bringing Light to the Dark Side of Insulin

“…Increased VMH GABAergic inhibitory tone. To assess whether increased VMH GABA tone contributes to the development of defective counterregulation, we quantified the GABA synthetic enzymes GAD 65 and GAD 67 within the VMH of rats exposed to recurrent hypoglycemia (53). These rodents demonstrated a specific increase in GAD 65 gene expression and a five-to sixfold increase in GAD 65 protein expression within the VMH.…”

Direct effects of recurrent hypoglycaemia on adrenal catecholamine release

“…Thus, our RH protocol reduces the sympatho-adrenal response to IIH, similar to previous reports. 15,[19][20][21]23,25 Adrenal CAT release evoked by splanchnic nerve stimulation after RH Most studies investigating the blunting of the EPI response produced by RH have focused on brain loci that regulate EPI secretion; 15,[19][20][21][22][23][24][25] however, much less is known about the effect of RH on the functional properties of peripheral components of the sympatho-adrenal axis. To address this issue, this study investigated adrenal CAT release in nondiabetic rats subjected to RH.…”